Topical drug delivery composition and method

ABSTRACT

A topical composition for delivering an effective amount of a pharmaceutically acceptable drug, including laureth-4, propylene glycol, dimethylsorbide, and a pharmaceutically acceptable diluent is described as an improved drug delivery composition. Further, a method of transepithelial delivery of a drug to a human by topical application to the skin of a human of a composition including laureth-4, propylene glycol, dimethylsorbide, a pharmaceutically acceptable diluent of water and ethanol and an effective amount of a pharmaceutically acceptable drug has beneficial delivery effects.

This is a continuation of application Ser. No. 08/199,989, filed Feb.22, 1994, which is a continuation of application Ser. No. 07/944,020,filed Sep. 11, 1992, which is a continuation of application Ser. No.07/677,375, filed Mar. 27, 1991, which is a continuation of applicationSer. No. 07/334,511, filed Apr. 6, 1989, all abandoned.

TECHNICAL FIELD

The present invention relates, in general, to a drug deliverycomposition and method, and, in particular, to a drug deliverycomposition and method for topical delivery of drugs, such as retinoids,which must be applied diligently and consistently to achieve optimal andreliable drug efficacy.

BACKGROUND OF THE INVENTION

It is to be understood that the citation of art contained herein is inno way to be construed as an admission that said art is suitablereference against the present patent application nor should thiscitation act as a waiver of any rights to overcome said art which may beavailable to the applicant.

The topical application of many active agents is desirable to achieveeffective concentrations of the agents at the target site. From apractical standpoint, however, skin preparations are often not appliedconscientiously by the user for a variety of reasons, and thus theoptimal results are frequently not achieved. Lack of user acceptanceoften results from the oiliness, tackiness, excessive film formation,odor, etc. that accompany many topical preparations. In addition,repeated exposure to certain topical delivery systems results inirritation or drying of the skin.

The continuous, i.e., daily, long-term, month-to-month, and consistenttopical application of at least one specific agent has recently beenreported to result in a reversal of photoaging of the skin. The agent,tretinoin (all trans-retinoic acid) was earlier reported to bebeneficial in the treatment of acne, seborrhea and psoriasis. Mostrecently Weiss and his co-workers have reported that tretinoin canimprove the effects of photoaging including wrinkling, sallowness,roughness and mottled pigmentation characteristic of photoaged skin whenapplied as a 0.1% cream daily for sixteen weeks. Weiss, J. S., et al.,Topical Tretinoin Improves Photoaged Skin: A Double-blindVehicle-Controlled Study, JAMA, 259:527-532, 1988. Similarly, Voorheesand co-workers have reported further and extended beneficial results maybe achieved from the consistent and continuous application of the 0.1%cream for a period in excess of fourteen months. FDC Reports, Vol. 9,No. 50, Dec. 12, 1988; Weiss, J. S., et al., Topical Tretinoin in theTreatment of Aging Skin, J. Am. Acad. Dermatol., 19:169-175, 1988.However, these researchers reported that most patients experiencedermatitis as a result of treatment with the tretinoin cream. Theinitial dermatitis, which is associated with xerosis, peeling Randsubjective irritation, lasts from two weeks to three months while asecond inflammatory phase, presumably of subclinical actinic keratosis,is experienced by some patients in which the erythema is more punctateor reticulate.

While the dermatitis reported by Weiss et al. and Voorhes appears toresult from the tretinoin itself, the results underscore the need for avehicle which enhances the absorption of the active agent so that thedesired end result can be achieved using a dose of the agent less likelyto cause irritation, as well as a vehicle which is favorably accepted bythe user so as to encourage and assure consistent, diligent andcontinuous use as directed.

Most topical drugs are administered on an outpatient basis. Thus, it isrequired that the patient apply the drug several times daily for thedrug to have its optimal effect. Because the drug is topically applied,it must be administered periodically due to washing or wearing off. Mostprior art delivery systems for topical drugs are not as pleasant as theycould be to the patient, in that the delivery vehicle itself, or itseffect upon the skin, is shiny, oily, tacky, drying, constricting,sweaty, greasy or malodorous. Because the drug delivery system is notpleasant, patients tend to stop using the drug, or do not use itaccording to the proper schedule. When the drug is not applied in theoptimal manner, because of the unpleasant delivery system, then thecondition for which the drug is applied is not optimally treated.

Thus, there is a need for a topical delivery system for drugs and otheractive agents that will encourage the consistent and continuousapplication needed to achieve optimal and reliable efficacy, and thatcan be comfortably used to deliver materials to the skin surface for thepurpose of providing epidermal, dermal and/or subcutaneous benefits.

SUMMARY OF THE INVENTION

The drug topical drug delivery composition and method of the presentinvention provides a method and composition that promotes a high degreeof patient compliance in encouraging their conscientious dailyapplication of active agents over months and years which produces morereliable and assured therapeutic results.

The topical drug delivery composition and method of the presentinvention also provides a new composition for delivering drugs and otheractive agents that has several desirable advantages in deliveringmaterials to the skin surface for the purpose of providing epidermal,dermal, subcutaneous and system benefits.

The composition and method of the present invention permits the deliveryvehicle to be imperceptible and invisible after application, thuseliminating the initial and residual oiliness, greasiness, tackiness,odor, color, shine and subjective annoyances and irritations of priorart vehicles.

The topical drug delivery composition of the present invention alsopermits the skin of the patient to become softened and smoothed ratherthan suffer from clinical problems often associated with other prior arttopical delivery vehicles, such as dry, cracked, red, irritated skin.

The composition of the present invention also permits the efficient andcontinuous release of active agents onto the surface of the skin and mayenhance penetration into the epidermis and underlying dermal andsubcutaneous tissues.

Thus, the present invention relates in general to a drug deliverycomposition comprising: i) an effective amount of a pharmaceuticallyacceptable surface tension reducing agent; ii) an effective amount of apharmaceutically acceptable skin hydrating agent; and iii) an effectiveamount of a hydrophilic-lipophilic coupling agent. In addition, thepresent invention may optionally contain a pharmaceutically acceptablediluent or carrier.

In another embodiment, the present invention relates to a topicalpreparation comprising the above-described delivery composition and anamount of a pharmaceutically acceptable retinoid sufficient to reversethe effects of aging such as wrinkling of skin.

The present invention further relates to a method of topicallydelivering a drug to the skin of an animal or human comprising the stepsof:

a) preparing a topical delivery composition comprising:

i) an effective amount of one or more pharmaceutically acceptablesurface tension reducing agents;

ii) an effective amount of one or more pharmaceutically acceptable skinhydrating agents;

iii) an effective amount of one or more hydrophilic-lipophilic couplingagents; and

iv) an effective amount of a pharmaceutically acceptable drug; and

b) applying the topical delivery composition to the skin of the animalor human.

The topical delivery composition of the method of the present inventionprovides a means with which to deliver a pharmacologically effectiveamount of one or more active ingredients. Furthermore, the topicaldelivery composition can contain an additional pharmaceuticallyacceptable carrier or diluent.

Accordingly, it is an object of the present invention to provide atopical drug delivery composition that promotes patient compliance byencouraging continuous and conscientious application of activeingredients on a schedule as directed, thus producing more reliable andassured therapeutic results.

It is a specific object of the present invention to provide a topicaldrug delivery composition wherein the vehicle is imperceptible andessentially invisible after application, thus eliminating initial andresidual oiliness, greasiness, excessive film formation, tackiness, odorand shine.

It is another object of the present invention to provide a topical drugdelivery composition that softens and soothes the skin and reducesclinical problems often associated with topical delivery vehicles, suchas dry, cracked, red, irritated skin without becoming aesthetically lessdesirable to the person using the formula.

It is another object of the present invention to provide a method ofeffecting the efficient and continuous release of active ingredientsinto and within the surface of the skin and, where desirable, furtherpenetration into the epidermis, and into the underlying dermal andsubcutaneous tissues.

It is another object of the present invention to provide pharmaceuticalcompositions suitable for topical delivery of retinoids whichsignificantly reduce the art-recognized problems associated withretinoid-containing compositions.

These and other objects, features and advantages of the presentinvention will become apparent after a review of the following detaileddescription of the disclosed embodiments and the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Thus, the present invention relates to a drug delivery compositioncomprising: i) an effective amount of a pharmaceutically acceptablesurface tension reducing agent; ii) an effective amount of apharmaceutically acceptable skin hydrating agent; and iii) an effectiveamount of a hydrophilic-lipophilic coupling agent. In addition, thepresent invention may optionally contain a pharmaceutically acceptablediluent or carrier.

The components of the topical drug delivery composition are preferablycolorless, clear or nondeleteriously tinted or colored andnonmalodorous, however, the final preparation may be colored, tinted orclear, as well as being scented or unscented as desired. Such aspects ascolor and scent of the final product can be selected such that theproduct's aesthetic appeal is enhanced. The invention further relates totopical preparations containing an active agent in association with sucha delivery composition.

The surface tension reducing agents of the invention include anionic,nonionic, cationic and amphoteric surfactants known in the art that are,when incorporated into the vehicle and applied to the skin, essentiallyclear, colorless and non-malodorous, and that are dermatologically safeand compatible with the active agents as well as the other vehicleingredients. The surface tension reducing agents can be used singly orin combination in a concentration ranging from approximately 0.001 to5.0% w/v, advantageously, in the range of approximately about 0.05 to1.5%. Suitable surface tension reducing agents include, but are notlimited to, laureth-4, octoxynol-9, cocoamphocarboxyglycinate, dioctylsodium sulfosuccinate and benzethonium chloride.

The skin softening agents of the invention include such agents known inthe art that are, when incorporated into the vehicle and applied to theskin, essentially clear, colorless, non-malodorous, and that aredermatologically safe and are compatible with the active agents as wellas the other vehicle ingredients. The skin softening agents can be usedsingly or in combination in a concentration ranging from approximately0.01 to 10.0% w/v, advantageously, in the range of from approximately0.05 to 5.0%. Skin softening agents suitable for use in the presentinvention include, by are not limited to, glycerin, propylene glycol,caprylic/capric triglyceride, pantothenol and its derivatives andrelated moieties, and hyaluronic acid and related moieties.

The hydrophilic-lipophilic coupling agents of the invention include suchagents known in the art that are when incorporated into the vehicle andapplied to the skin essentially clear, colorless, non-malodorous, andthat are dermatologically safe and compatible with the active, and othervehicle, ingredients. The hydrophilic-lipophilic coupling agents can beused singly or in combination in concentrations ranging fromapproximately 0.01 to 5.0% w/v, advantageously, in the range ofapproximately 0.05 to 2.5%. Hydrophilic-lipophilic coupling agentsinclude, but are not limited to, dimethylisosorbide, diisopropyladipate, dioctyl maleate, propylene carbonate, diisopropyl sebacate and1-dodecylazacycloheptan-2-one (See U.S. Pat. No. 3,989,816) (Sold underthe tradename Azone, Nelson Research and Development Company, IrvineCalif.).

The solvents and carrying agents of the invention include such agentsknown in the art that are when incorporated into the vehicle and appliedto the skin clear, colorless, volatile, non-malodorous and comfortable,that are dermatologically safe, and that are compatible with the activeagents and other vehicle ingredients. The solvents and carrying agentscan be used singly or in combination in concentration ranges suitable tobring the vehicle and active components up to the desired finalstrength. Solvents and carrying agents suitable for use in the presentinvention include, but are not limited to, ethyl alcohol, partially orfully deodorized alcohols and iso-alcohols, suitable denatured alcohols,methanol, water ketones, esters, ethers and the like. Advantageously,the alcohols are used at concentrations that are close to or below theirminimal, antimicrobial inhibitory concentrations, because, at suchconcentrations, they possess better subjective qualities and minimaladverse skin acceptance problems, such as stinging. Thus, for example,concentrations of ethyl alcohol in the range of approximately 30% to 45%v/v are advantageous.

The drug delivery composition of that invention can also contain agentsthat chemically, physically and/or microbiocidally stabilize the activeand other ingredients, agents that introduce aesthetically pleasingcharacteristics, and/or agents that protect the skin from ultra-violetand other radiation, free radicals and other internal and externalinsults. Such agents include preservatives, anti-oxidants, ultra-violetand radiation absorbing agents, free-radical inhibiting, quenching orneutralizing agents (for example tocopherol or derivatives thereof),colors, fragrances and the like. Effective concentrations of such agentsare well known in the art or can readily be determined by one skilled inthe art.

Active ingredients that can be included in the above-described deliverycomposition include, but are not limited to, retinoids, including transand 13-cis retinoic acids, retinol, retinyl esters, and otherphysiologically active retinoid derivatives such as etretinate;steroidal, non-steroidal, retinoidal and other anti-inflammatories, suchas hydrocortisone, dexamethasone, betamethasone and other steroids;non-steroidal antiinflammatories including ibuprofen and indomethacin;antibiotics such as erythromycin, ampicillin and clindamycin; antiviralagents such as acyclovir; agents such as antifungals, antimitotics,anesthetics, antihistamines, antibacterials, antipsoriatics,keratolytic, depigmenting and emollients; and agents that eitherstimulate, normalize or beneficially modify cellular formation anddifferentiation.

This invention is further illustrated by the following examples, whichare not to be construed in any way as imposing limitations upon thescope thereof. On the contrary, it is to be clearly understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which, after reading the description herein, maysuggest themselves to those skilled in the art without departing fromthe spirit of the present invention and/or the scope of the appendedclaims.

EXAMPLE I

The following is a specific example of three alternative formulations ofthe topical delivery composition of the present invention as describedin general terms above.

    ______________________________________                                        Formulation 1                                                                     Laureth-4            1.0%    w/v                                            Glycerin 2.0% w/v                                                             Propylene Glycol 2.0% w/v                                                     Dimethylisosorbide 0.5% w/v                                                   Ethanol 35.00% v/v                                                            Preservatives  as needed                                                      Water  to final volume                                                      Formulation 2                                                                     Octoxynol-9          0.05%   w/v                                            Glycerin 2.40% w/v                                                            Propylene Glycol 0.60% w/v                                                    Dioctyl Maleate 1.00% w/v                                                     Ethanol 28.50% v/v                                                            Preservatives  as needed                                                      Water  to final volume                                                      Formulation 3                                                                     Cocoamphocarboxyglycinate                                                                          0.35%   w/v                                            Caprylic/Capric Triglyceride 0.25% w/v                                        Propylene Glycol 2.00% w/v                                                    Dimethylisosorbide 1.00% w/v                                                  Ethanol 40.00% w/v                                                            Pantothenol 0.25% v/v                                                         Preservatives  as needed                                                      UV A, B and other radiation screens  as needed                                Free radical inhibitors or quenchers  as needed                               Water  to final volume                                                      ______________________________________                                    

EXAMPLE II

The following is an example of a composition contemplated as oneembodiment of the present invention containing a pharmaceuticallyacceptable retinoid sufficient to reverse the effects of aging upon theskin including wrinkling.

Formulation A contains 0.005% trans-retinoic acid whereas Formulation Bcontains 0.010% trans-retinoic acid and Formulation C contains 0.050%trans-retinoic acid.

    ______________________________________                                                           Formulation A                                                 0.005%                                                                        trans-retinoic acid                                                        ______________________________________                                          Butylated hydroxytoluene 0.015%                                               Disodium EDTA 0.015%                                                          Laureth-4 (Brij 30) 1.00%                                                     Glycerin 2.00%                                                                Propylene Glycol 3.00%                                                        1-dodecylazacycloheptan-2-one 0.10%                                           trans-retinoic acid 0.00625%                                                   [0.005% + 20% excess]                                                        SD-40 Ethanol, 95% v/v 38.50%                                                 Purified Water (distilled/deionized) Q.S.                                      [55.36375%]                                                                ______________________________________                                           Formulation B                                                                 0.010%                                                                        trans-retinoic acid                                                        ______________________________________                                          Butylated hydroxytoluene 0.015%                                               Disodium EDTA 0.015%                                                          Laureth-4 (Brij 30) 1.00%                                                     Glycerin 2.00%                                                                Propylene Glycol 3.00%                                                        1-dodecylazacycloheptan-2-one 0.20%                                           trans-retinoic acid 0.0120%                                                    [0.010% + 20% excess]                                                        SD-40 Ethanol, 95% v/v 43.50%                                                 Purified Water (distilled/deionized) Q.S.                                      [50.258%]                                                                  ______________________________________                                           Formulation C                                                                 0.050%                                                                        trans-retinoic acid                                                        ______________________________________                                          Butylated hydroxytoluene 0.015%                                               Disodium EDTA 0.015%                                                          Laureth-4 (Brij 30) 1.00%                                                     Glycerin 2.00%                                                                Propylene Glycol 3.00%                                                        1-dodecylazacycloheptan-2-one 1.00%                                           trans-retinoic acid 0.0625%                                                    [0.050% + 20% excess]                                                        SD-40 Ethanol, 95% v/v 48.50%                                                 Purified Water (distilled/deionized) Q.S.                                      [44.4075%]                                                                 ______________________________________                                    

EXAMPLE III

The following is an example of a composition contemplated as oneembodiment of the present invention containing a pharmaceuticallyacceptable retinoid sufficient to reverse the effects of aging upon theskin such as wrinkling.

Formulation A contains 0.005% trans-retinoic acid whereas Formulation Bcontains 0.010% trans-retinoic acid and Formulation C contains 0.050%trans-retinoic acid.

    ______________________________________                                                           Formulation A                                                 0.005%                                                                        trans-retinoic acid                                                        ______________________________________                                          Butylated hydroxytoluene 0.015%                                               Disodium EDTA 0.015%                                                          Laureth-4 (Brij 30) 1.00%                                                     Glycerin 2.00%                                                                Propylene Glycol 2.00%                                                        Dimethylisosorbide 0.50%                                                      Alpha tocopherol 0.01%                                                        trans-retinoic acid 0.00625%                                                   [0.005% + 20% excess]                                                        SD-40 Ethanol, 95% v/v 38.50%                                                 Purified Water (distilled/deionized) Q.S.                                      [55.95375%]                                                                ______________________________________                                           Formulation B                                                                 0.010%                                                                        trans-retinoic acid                                                        ______________________________________                                          Butylated hydroxytoluene 0.015%                                               Disodium EDTA 0.015%                                                          Laureth-4 (Brij 30) 1.00%                                                     Glycerin 2.00%                                                                Propylene Glycol 2.00%                                                        Dimethylisosorbide 0.50%                                                      Alpha tocopherol 0.01%                                                        trans-retinoic acid 0.0120%                                                    [0.010% + 20% excess]                                                        SD-40 Ethanol, 95% v/v 38.50%                                                 Purified Water (distilled/deionized) Q.S.                                      [55.948%]                                                                  ______________________________________                                           Formulation C                                                                 0.050%                                                                        trans-retinoic acid                                                        ______________________________________                                          Butylated hydroxytoluene 0.015%                                               Disodium EDTA 0.015%                                                          Laureth-4 (Brij 30) 1.00%                                                     Glycerin 2.00%                                                                Propylene Glycol 2.00%                                                        Dimethylisosorbide 0.50%                                                      Alpha tocopherol 0.01%                                                        trans-retinoic acid 0.0625%                                                    [0.050% + 20% excess]                                                        SD-40 Ethanol, 95% v/v 38.50%                                                 Purified Water (distilled/deionized) Q.S.                                      [55.8975%]                                                                 ______________________________________                                    

EXAMPLE IV

The composition containing trans-retinoic acid as described inFormulation A in Example II above is compared to a prior art compositioncontaining all trans-retinoic acid (See U.S. Pat. No. 3,906,108). Theprior art composition described in that patent is as follows:

    ______________________________________                                        Ingredient          grams                                                     ______________________________________                                        Tretinoin (All trans-retinoic acid)                                                               0.1                                                         Xanthan Gum, food grade 0.3                                                   Polyoxy stearate, USP 5.0                                                     Stearyl alcohol, USP 3.0                                                      Stearic acid, USP 19.0                                                        Isopropyl myristate, CTFA 10.0                                                Butylated hydroxytoluene 0.1                                                  Sorbic acid, NF 0.2                                                           Purified Water, USP q.s. to 100.0 ml                                        ______________________________________                                    

The experiment is a double blind study. The test material is appliedonce each evening to the face for 12 months. Forty patients are enrolledinto the study. Patients are assigned either the composition describedas Formulation A in Example II above or the prior art compositiondescribed above.

After 6 months, the group using the composition described as FormulationA in Example II above shows a significantly lower drop out rate thandoes the group using the composition described in the prior art.

EXAMPLE V

An experiment is performed to demonstrate that the improved topical drugdelivery composition of the present invention increases the efficacy ofthe pharmaceutically active ingredient tretinoin. Two formulations ofthe composition shown in Example II (containing 0.005% and 0.010%trans-retinoic acid) are compared to a prior art tretinoin gelcomposition. The ability of each vehicle to cause skin penetration ofthe active ingredient is analyzed.

The composition of the tretinoin gel is as follows: Approximately 0.010to 0.025% tretinoin (trans-retinoic acid), approximately 1.0%hydroxypropyl cellulose, approximately 0.1% butylated hydroxytoluene,approximately 90% w/w Ethyl Alcohol and purified water.

When the skin penetration performance of the two formulations set forthin Example II (containing 0.005% and 0.010% trans-retinoic acid) arecompared to that of the more potent tretinoin gel (containing 0.01%trans-retinoic acid), the penetration of each formulation set forth inExample II is greater by at least a factor of two than that of the 0.01%commercial tretinoin gel.

EXAMPLE VI

The effect of retinoids on the turnover time of the stratum cornium isassessed in vivo using the dansyl chloride method. The dansyl chloridemethod is known to those skilled in the art and is recognized as ameasurement of biological activity. The biological activity of theembodiment of the composition of the present invention set forth abovein Example II is compared with the prior art tretinoin gel compositiondescribed above in Example V.

The results show that the two formulations described in Example II(containing 0.005% and 0.010% trans-retinoic acid) induce an increase inregeneration time greater than that achieved by commercial tretinoin gelcontaining 0.01% trans-retinoic acid.

It should be understood, of course, that the foregoing relates only to apreferred embodiments of the present invention and that numerousmodifications or alterations may be made therein without departing fromthe spirit and the scope of the invention as set forth in the appendedclaims.

We claim:
 1. A topical composition consisting essentially of:i)laureth-4, present in about 1 percent by weight of the totalcomposition; ii) propylene glycol, present in about 2 percent by weightof the total composition; iii) dimethylsorbide, present in about 0.5percent by weight of the total composition; iv) trans-retinoic acid,present in about 0.01 percent by weight of the total composition; and v)a pharmaceutically acceptable diluent comprising a mixture of water andethanol.
 2. A method for transepithelial delivery of trans-retinoic acidto a human, comprising applying to the skin of the human a topicalcomposition consisting essentially ofi) laureth-4, present in about 1percent by weight of the total composition; ii) propylene glycol,present in about 2 percent by weight of the total composition; iii)dimethylsorbide, present in about 0.5 percent by weight of the totalcomposition; iv) trans-retinoic acid, present in about 0.01 percent byweight of the total composition; and v) a pharmaceutically acceptablediluent comprising a mixture of water and ethanol.
 3. A topicalcomposition consisting essentially of:i) laureth-4, present in about 1percent by weight of the total composition; ii) propylene glycol,present in about 2 percent by weight of the total composition; iii)dimethylsorbide, present in about 0.5 percent by weight of the totalcomposition; iv) an effective amount of a pharmaceutically acceptabledrug, wherein the drug is effective when administered topically; and v)a pharmaceutically acceptable diluent comprising a mixture of water andethanol.
 4. A method for transepithelial delivery of a drug to a human,comprising applying to the skin of the human a topical compositionconsisting essentially of:i) laureth-4, present in about 1 percent byweight of the total composition; ii) propylene glycol, present in about2 percent by weight of the total composition; iii) dimethylsorbide,present in about 0.5 percent by weight of the total composition; iv) aneffective amount of a pharmaceutically acceptable drug, wherein the drugis effective when administered topically; and v) a pharmaceuticallyacceptable diluent comprising a mixture of water and ethanol.
 5. Atopical composition consisting essentially of:i) SDA-40 200 proof,present in about 36.8 percent by weight of the total composition; i)butylated hydroxyanisole, present in about 0.15 percent by weight of thetotal composition; ii) glycerin, present in about 2 percent by weight ofthe total composition; iv) propylene glycol, present in about 2 percentby weight of the total composition; v) purified distilled water, presentin about 40 percent by weight of the total composition; vi) pantethine,present in about 0.03 percent by weight of the total composition; vii)laureth-4, present in about 1 percent by weight of the totalcomposition; viii) dimethylsorbide, present in about 0.5 percent byweight of the total composition; ix) disodium EDTA, present in about0.15 percent by weight of the total composition; and v) distilled water.6. The composition of claim 5 further comprising a pharmaceuticallyactive drug, wherein the drug is effective when administered topically.7. The composition of claim 6 wherein that drug is trans-retinoic acid.8. A method for transepithelial delivery of a drug to a human,comprising applying to the skin of the human a topical compositionconsisting essentially of:i) SDA-40 200 proof present in about 36.8percent by weight of the total composition; ii) butylatedhydroxyanisole, present in about 0.15 percent by weight of the totalcomposition; iii) glycerin USP 96 percent, present in about 2 percent byweight of the total composition; iv) propylene glycol, present in about2 percent by weight of the total composition; v) purified distilledwater, present in about 40 percent by weight of the total composition;vi) pantethine 80 percent, present in about 0.03 percent by weight ofthe total composition; vii) laureth-4, present in about I percent byweight of the total composition; viii) dimethylsorbide, present in about0.5 percent by weight of the total composition; ix) disodium EDTA,present in about 0.15 percent by weight of the total composition; x) apharmaceutically active drug, wherein the drug is effective whenadministered topically; and xi) distilled water.
 9. The composition ofclaim 8 wherein that drug is trans-retinoic acid.